阿托伐他汀合成图解

【药物名称】
Atorvastatin calcium, YM-548, CI-981, Prevencor, Tahor, Lipibec, Torvast, Sortis, Lipitor
【化学名】
(3R,5R)-7-[2-(4-Fluorophenyl)-5-isopropyl-3-phenyl-4-(phenylcarbamoyl)pyrrol-1-yl]-3,5-dihydroxyheptanoic acid calcium salt (2:1) 【CAS登记号】
134523-03-8, 134523-00-5 (free acid), 110862-48-1 (free acid (R*,R*)-isomer)
【结构式】
【分子式】
2-C33-H34-F-N2-O5.Ca
【分子量】
1155.355
【原研厂家】
Jouveinal (Originator), Pfizer (Originator), Almirall Prodesfarma (Licensee), Syncro (Licensee), Yamanouchi (Licensee), Stanford University (Codevelopment)
【作用类别】
Alzheimer's Dementia, Treatment of , CARDIOVASCULAR DRUGS, Cognition Disorders, Treatment of, Immunologic Neuromuscular Disorders, Treatment of, Lipoprotein Disorders, Treatment of , METABOLIC DRUGS, Multiple Sclerosis, Agents for, NEUROLOGIC DRUGS, Treatment of Disorders of the Coronary Arteries and Atherosclerosis, HMG-CoA Reductase Inhibitors, TNFSF6 Expression Inhibitors
【研发状态】
Launched-1997
【合成情况】
NB2
〖来源〗
Drugs Fut
〖合成路线〗
〖标题〗
Atorvastatin Calcium
〖合成方法〗
1) The condensation of 2-(1,3-dixolan-2-yl)ethylamine (I) with ethyl 2-bromo-2-(4-fluorophenyl)acetate (II) by means of triethylamine in acetonitrile gives ethyl 2-[2-(1,3-dioxolan-2-yl)ethylamino]-2-(4-fluorophenyl)acetate (III), which is acylated with isobutyryl chloride (IV) and triethylamine in dichloromethane yielding the corresponding amide (V). Saponification of the ester (V) with NaOH in methanol/water affords the free acid (VI), which is cyclized with N,3-diphenylpropynamide (VII) [obtained in the reaction of 3-phenylpropynoic acid (VIII) with aniline (IX) by means of dicyclohexylcarbodiimide (DCC)] by heating at 90 C in acetic anhydride giving
1-[2-(1,3-dioxolan-2-yl)ethyl]-5-(4-fluorophenyl)-2-isopropyl-N,4-diphenylpyrrole-3-carboxamide (X). The hydrolysis of the dioxolane group of (X) with HCl yields the corresponding aldehyde (XI), which is condensed with methyl acetoacetate (XII) by means of NaH in THF affording 7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-(N-phenylcarbamoyl)pyrrol-1-yl]-5-hydroxy-3-oxoheptanoic acid methyl ester (XIII). The reduction of the carbonyl group of (XIII) with tributylborane and NaBH4 in THF gives the (3R*,5R*)-dihydroxy ester (XIV), which is saponified with NaOH in water yielding the corresponding free acid (XV). The lactonization of (XV) by heating in refluxing toluene affords the (R*,R*)-lactone (XVI), which is submitted to optical resolution by reaction with (R)-1-phenylethylamine (XVII) followed by fractional crystallization thus obtaining the amide (XVII) as the pure (R,R,R)-enantiomer. The hydrolysis of the amide (XVIII) with NaOH, followed by heating in refluxing toluene gives the (R,R)-lactone (XIX), which is finally treated first with NaOH in methanol/water, and then with CaCl2 or calcium acetate.
〖作者〗
Graul, A.; Casta馿r, J.
〖参考〗
Graul, A.; Casta馿r, J.; Atorvastatin Calcium. Drugs Fut 1997, 22, 9, 956
〖出处〗
Drugs Fut1997,22,(9):956
〖备注〗
Synthesis Atorvastatin calcium has been obtained by several different ways: 1) The condensation of 2-(1,3-dixolan-2-yl)ethylamine (I) with ethyl 2-bromo-2-(4-fluorophenyl)acetate (II) by means of triethylamine in acetonitrile gives ethyl
2-[2-(1,3-dioxolan-2-yl)ethylamino]-2-(4-fluorophenyl)acetate (III), which is acylated with isobutyryl chloride (IV) and triethylamine in dichloromethane yielding the corresponding amide (V). Saponification of the ester (V) with NaOH in methanol/water affords the free acid (VI), which is cyclized with N,3-diphenylpropynamide (VII) [obtained in the reaction of 3-phenylpropynoic acid (VIII) with aniline (IX) by means of dicyclohexylcarbodiimide (DCC)] by heating at 90 癈in acetic anhydride giving
1-[2-(1,3-dioxolan-2-yl)ethyl]-5-(4-fluorophenyl)-2-isopropyl-N,4 -diphenylpyrrole-3-carboxamide (X). The hydrolysis of the dioxolane group of (X) with HCl yields the corresponding aldehyde (XI), which is condensed with methyl acetoacetate (XII) by means of NaH in THF affording 7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-(N-phenylcarbamoyl)pyrrol -1-yl]-5-hydroxy-3-oxoheptanoic acid methyl ester (XIII). The reduction of the carbonyl group of (XIII) with tributylborane and NaBH4 in THF gives the (3R*,5R*)-dihydroxy ester (XIV), which is saponified with NaOH in water yielding the corresponding free acid (XV). The lactonization of (XV) by heating in refluxing toluene affords the (R*,R*)-lactone (XVI) (1, 2), which is submitted to optical resolution by reaction with (R)-1-phenylethylamine (XVII) followed by fractional crystallization thus obtaining the amide (XVII) as the pure (R,R,R)-enantiomer. The hydrolysis of the amide (XVIII) with NaOH, followed by heating in refluxing toluene gives the (R,R)-lactone (XIX) (2, 3), which is finally treated first with NaOH in
methanol/water, and then with CaCl2 or calcium acetate (3, 4). 2) The condensation of the already described aldehyde (XI) with
(S)-(+)-2-acetoxy-1,1,2-triphenylethanol (XX) by means of lithium diisopropylamide (LDA) in THF gives
5-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-(N-phenylcarbamoyl)pyrrol -1-yl]-3(R)-hydroxypentanoic acid
2-hydroxy-1(S),2,2-triphenylethyl ester (XXI), which is trans-esterified with sodium methoxide in methanol/THF yielding the expected methyl ester (XXII). The condensation of (XXII) with tert-butyl acetate (XXIII) by means of LDA in THF affords
(R)-7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-(N-phenylcarbamoyl) pyrrol-1-yl]-5-hydroxy-3-oxoheptanoic acid tert-butyl ester (XXIV), which is reduced with triethylborane and NaBH4 in THF, hydrolyzed with NaOH, lactonized by heating in refluxing toluene and finally submitted to fractional crystallization in order to separate the two diastereomers of the obtained lactone, (R,R) and (R,S) (2, 3). The
(R,R)-diastereomer (XIX), already obtained, is finally treated with NaOH and then with CaCl2 (2-4). 3) The condensation of
4-cyano-3(R)-hydroxybutyric acid ethyl ester (XXV) with N,N-diphenylacetamide (R1 = R2 = Ph in XXVI) by means of LDA in THF gives 6-cyano-5(R)-hydroxy-3-oxo-N,N-diphenylhexanamide (XXVII), which is reduced with diethylmethoxyborane and NaBH4 in THF yielding 6-cyano-3(R),5(R)-dihydroxy-N,N-diphenylhexanamide (XXVIII). The protection of the two OH groups of (XXVIII) with acetone dimethylketal (XXIX) and methanesulfonic acid affords the 1,3-dioxane (XXX), which by reduction of its CN group by hydrogenation with H2 over RaNi in methanol/liquid ammonia gives (4R,6R)-2-[6-(2-aminoethyl)-2,2-dimethyl-1,3-dioxan-4-yl]-N,N -diphenylacetamide (XXXI). The cyclization of (XXXI) with 4-(4-fluorophenyl)-2-isobutyryl-4-oxo-N-phenylbutyramide (XXXII) (its synthesis is in section 6, Scheme 4) in refluxing toluene yields the protected dihydroxyheptanamide (XXXIII), which is deprotected with HCl in methanol to afford (3R,5R)-7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-(N -phenylcarbamoyl)pyrrol-1-yl]-3,5-dihydroxy-N,N-diphenylheptanamide (XXXIV). Finally, this compound is hydrolyzed with NaOH and treated with calcium acetate in water (5). Scheme 18007203a. 4) The preceding reaction pathway can be repeated using other substituents for R1 and R2 in acetamide (XXVI) such as R1 = R2 = CH2Ph; R1 = R2 = Et; R1 = Bu, R2 = Me; R1 = t-Bu, R2 = CH2Ph; R1,R2 = -(CH2)5- (5). 5) The hydrolysis of methyl (Et or Bu)
3(R)-(tert-butyldimethylsilyloxy)-4-cyanobutyrate (XXV) with NaOH gives the corresponding free acid (XXXVI), which is condensed with malonic acid mono-tert-butyl ester magnesium salt (XXXVII) by means of carbonyldiimidazole (CDI) yielding tert-butyl
5(R)-(tert-butyldimethylsilyloxy)-6-cyano-3-oxohexanoate (XXXVIII). The desilylation of (XXXVIII) with tetrabutylammonium fluoride in acetic acid affords the expected hydroxylated ketoester (XXXIX), which is reduced with diethylmethoxyborane and NaBH4 in methanol giving tert-butyl 6-cyano-3(R),5(R)-dihydroxyhexanoate (XL). The protection of the two OH groups of (XL) with acetone dimethylketal
(XXIX) and methanesulfonic acid affords the 1,3-dioxane (XLI) (6), which by reduction of its CN group by hydrogenation with H2 over
Pd/C gives intermediate (4R,6R)-2-[6-(2-aminoethyl)-2,2-dimethyl-1,3-dioxan-4-yl]acetic acid tert-butyl ester (XLII). The cyclization of (XLII) with 4-(4-fluorophenyl-2-isobutyryl-4-oxo-N-phenylbutyramide (XXXII) in refluxing toluene yields the protected dihydroxyheptanoate (XLIII), which is deprotected with HCl in methanol and finally hydrolyzed with NaOH and treated with calcium acetate in water (7). 8) The synthesis of the 4-(4-fluorophenyl)-2-isobutyryl-4-oxo-N-phenylbutyramide (XXXII) is carried out as follows: The condensation of 4-methyl-3-oxo-N-phenylpentanamide (XLIV) with benzaldehyde (XLV) gives
2-benzylidene-4-methyl-3-oxo-N-phenylpentanamide (XLVI), which is then condensed with 4-fluorobenzaldehyde (XLVII) by means of triethylamine in hot ethanol (7). 6) The (4R,6R)-2-[6-(cyanomethyl)-2,2-dimethyl-1,3-dioxan-4-yl]acetic acid tert-butyl ester (XLI) can also be obtained by reaction of (4R,6R)-2-[6-(2-hydroxyethyl)-2,2-dimethyl-1,3-dioxan-4-yl]acetic acid tert-butyl ester (XLVIII) with tosyl chloride to give the corresponding tosylate (XVIX), which is then treated with NaCN (6). 7) The tert-butyl
6-cyano-5(R)-hydroxy-3-oxohexanoate (XXXIX) can also be obtained by condensation of methyl 4-cyano-3(R)-hydroxybutyrate (L) with tert-butyl acetate (XXIII) by means of LDA in THF (6). 8) The synthesis of the 4-(4-fluorophenyl)-2-isobutyryl-4-oxo-N-phenylbutyramide (XXXII) is carried out as follows: The condensation of 4-methyl-3-oxo-N-phenylpentanamide (XLIV) with benzaldehyde (XLV) gives
2-benzylidene-4-methyl-3-oxo-N-phenylpentanamide (XLVI), which is then condensed with 4-fluorobenzaldehyde (XLVII) by means of triethylamine in hot ethanol (7). 9) The cyclization of (XXXII) with intermediate (XLII) (preceding synthesis) in refluxing toluene yields the protected dehydroxyheptanoate (XLIII), which is deprotected with HCl in methanol and finally hydrolyzed with NaOH and treated with calcium acetate in water. References 1. Roth, B.D. (Warner-Lambert Co.). Trans-6-[2-(3- or 4-carboxamido-substd.
pyrrol-1-yl)alkyl]-4-hydroxypyran-2-one inhibitors of cholesterol synthesis. EP 247633, US 4681893. 2. Roth, B.D., Blankley, C.J., Chucholowski, A.W., Ferguson, E., Hoefle, M.L., Ortwine, D.F., Newton, R.S., Sekerke, C.S., Sliskovic, D.R., Stratton, C.D., Wilson, M.W. Inhibitors of cholesterol biosynthesis. 3. Tetrahydro-4-hydroxy-6-[2-(1H-pyrrol-1-yl)ethyl]-2H-pyran-2-one inhibitors of HMG-CoA reductase. 2. Effects of introducing substituents at positions three and four of the pyrrole nucleus. J Med Chem 1991, 34: 357-66. 3. Roth, B.D. (Warner-Lambert Co.). (R-(R*R*)-2-(4-Fluorophenyl)-beta,delta-dihydroxy-5-(1-methylethyl-3
-phenyl-4-[(phenylamino)-carbonyl]-1H-pyrrole-1-heptanoic acid, its lactone form and salts thereof. EP 409281, JP 91058967, US 5273995.
4. Milb, N., Muhammad, N.A., Weiss, J., Nesbitt, R.U. (Warner-Lambert Co.). Stable oral CI-981 formulation and process for preparing same. EP 680320, JP 96505640, WO 9416693.
5. Butler, D.E., Le, T.V., Nanninga, T.N. (Warner-Lambert Co.). Process for
trans-6-[2-(substd.-pyrrol-1-yl)alkyl]pyran-2-one inhibitors of cholesterol synthesis. US 5298627. 6. Brower, P.L., Butler, D.E., Deering, C.F., Le, T.V., Millar, A., Nanninga, T.N., Roth, B.D. The synthesis of (4R-cis)-1,1-dimethylethyl
6-cyanomethyl-2,2-dimethyl-1,3-dioxane-4-acetate, a key intermediate for the preparation of CI-981, a highly potent, tissue selective inhibitor of HMG-CoA reductase. Tetrahedron Lett 1992, 33: 2279-82. 7. Baumann, K.L., Butler, D.E., Deering, C.F., Mennen, K.E., Millar, A., Nanninga, T.N., Palmer, C.W., Roth, B.D. The convergent synthesis of CI-981, an optically active, highly potent, tissue selective inhibitor of HMG-CoA reductase. Tetrahedron Lett 1992, 33: 2283-4. 8. McKenzie, A.T. (Warner-Lambert Co.). Form III crystalline
(R-(R*,R*))-2-(4-fluorophenyl)-beta,delta-dihydroxy-5-(1-methyl-ethyl) -3-phenyl-4-((phenylamino)carbonyl)-1H-pyrrole-1-heptanoic acid hemi calcium salt (atorvastatin). WO 9703958. 9. Lin, M., Schweiss, D. (Warner-Lambert Co.). Novel process for the production of amorphous [R-(R*,R*)]-2-(4-fluorophenyl)-beta,delta-dihydroxy-5-(1-methylethyl)
-3-phenyl-4-[(phenylamino)carbonyl]-1H-pyrrole-1-heptanoic acid calcium salt (2:1). WO 9703960. 10. Briggs, C.A., Jennings, R.A., Wade, R.A., Harasawa, K., Ichikawa, S., Minohara, K., Nakagawa, S. (Warner-Lambert Co.). Crystalline
[R-(R*,R*)]-2-(4-fluorophenyl)-beta,delta-dihydroxy-5-(1-methylethyl) -3-phenyl-4-[(phenylamino)carbonyl]-1H-pyrrole-1-heptanoic acid hemi calcium salt (atorvastatin). WO 9703959.
〖来源〗
J Med Chem
〖合成路线〗
〖标题〗
Inhibitors of cholesterol biosynthesis. 3. Tetrahydro-4-hydroxy-6-[2-(1H-pyrrol-1-yl)ethyl]-2H-pyran-2-one inhibitors of HMG-CoA reductase. 2. Effects of introducing substituents at positions three and four of the pyrrole nucleus
〖合成方法〗
1) The condensation of 2-(1,3-dixolan-2-yl)ethylamine (I) with ethyl 2-bromo-2-(4-fluorophenyl)acetate (II) by means of triethylamine in acetonitrile gives ethyl 2-[2-(1,3-dioxolan-2-yl)ethylamino]-2-(4-fluorophenyl)acetate (III), which is acylated with isobutyryl chloride (IV) and triethylamine in dichloromethane yielding the corresponding amide (V). Saponification of the ester (V) with NaOH in methanol/water affords the free acid (VI), which is cyclized with N,3-diphenylpropynamide (VII) [obtained in the reaction of 3-phenylpropynoic acid (VIII) with aniline (IX) by means of dicyclohexylcarbodiimide (DCC)] by heating at 90 C in acetic anhydride giving
1-[2-(1,3-dioxolan-2-yl)ethyl]-5-(4-fluorophenyl)-2-isopropyl-N,4-diphenylpyrrole-3-carboxamide (X). The hydrolysis of the dioxolane group of (X) with HCl yields the corresponding aldehyde (XI), which is condensed with methyl acetoacetate (XII) by means of NaH in THF affording 7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-(N-phenylcarbamoyl)pyrrol-1-yl]-5-hydroxy-3-oxoheptanoic acid methyl ester (XIII). The reduction of the carbonyl group of (XIII) with tributylborane and NaBH4 in THF gives the (3R*,5R*)-dihydroxy ester (XIV), which is saponified with NaOH in water yielding the corresponding free acid (XV). The lactonization of (XV) by heating in refluxing toluene affords the (R*,R*)-lactone (XVI), which is submitted to optical resolution by reaction with (R)-1-phenylethylamine (XVII) followed by fractional crystallization thus obtaining the amide (XVII) as the pure (R,R,R)-enantiomer. The hydrolysis of the amide (XVIII) with NaOH, followed by heating in refluxing toluene gives the (R,R)-lactone (XIX), which is finally treated first with NaOH in methanol/water, and then with CaCl2 or calcium acetate.
〖作者〗
Roth, B.D.; Blankley, C.J.; Chucholowski, A.W.; Ferguson, E.; Hoefle, M.L.; Ortwine, D.F.; Newton, R.S.; Sekerke, C.S.; Sliskovic, D.R.; Stratton, C.D.; Wilson, M.W.
〖参考〗
Roth, B.D.; Blankley, C.J.; Chucholowski, A.W.; Ferguson, E.; Hoefle, M.L.; Ortwine, D.F.; Newton, R.S.; Sekerke, C.S.; Sliskovic, D.R.; Stratton, C.D.; Wilson, M.W.; Inhibitors of cholesterol biosynthesis. 3. Tetrahydro-4-hydroxy-6-[2-(1H-pyrrol-1-yl)eth IĶ 셈睋서睋쓰睎
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〖出处〗
J Med Chem1991,34,(1):357-66
〖备注〗
〖来源〗
Drugs Fut
〖合成路线〗
〖标题〗
Atorvastatin Calcium
〖合成方法〗
2) The condensation of the previously described aldehyde (XI) with (S)-(+)-2-acetoxy-1,1,2-triphenylethanol (XX) by means of lithium diisopropylamide (LDA) in THF gives
5-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-(N-phenylcarbamoyl)pyrrol-1-yl]-3(R)-hydroxypentanoic acid
2-hydroxy-1(S),2,2-triphenylethyl ester (XXI), which is trans-esterified with sodium methoxide in methanol/THF yielding the expected methyl ester (XXII). The condensation of (XXII) with tert-butyl acetate (XXIII) by means of LDA in THF affords
(R)-7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-(N-phenylcarbamoyl) pyrrol-1-yl]-5-hydroxy-3-oxoheptanoic acid tert-butyl ester (XXIV), which is reduced with triethylborane and NaBH4 in THF, hydrolyzed with NaOH, lactonized by heating in refluxing toluene and finally submitted to fractional crystallization in order to separate the two diastereomers of the obtained lactone, (R,R) and (R,S). The
(R,R)-diastereomer (XIX), already obtained, is finally treated with NaOH and then with CaCl2.
〖作者〗
Graul, A.; Casta馿r, J.
〖参考〗
Graul, A.; Casta馿r, J.; Atorvastatin Calcium. Drugs Fut 1997, 22, 9, 956
〖出处〗
Drugs Fut1997,22,(9):956
〖备注〗
Synthesis Atorvastatin calcium has been obtained by several different ways: 1) The condensation of 2-(1,3-dixolan-2-yl)ethylamine (I) with ethyl 2-bromo-2-(4-fluorophenyl)acetate (II) by means of triethylamine in acetonitrile gives ethyl
2-[2-(1,3-dioxolan-2-yl)ethylamino]-2-(4-fluorophenyl)acetate (III), which is acylated with isobutyryl chloride (IV) and triethylamine in dichloromethane yielding the corresponding amide (V). Saponification of the ester (V) with NaOH in methanol/water affords the free acid (VI), which is cyclized with N,3-diphenylpropynamide (VII) [obtained in the reaction of 3-phenylpropynoic acid (VIII) with aniline (IX) by means of dicyclohexylcarbodiimide (DCC)] by heating at 90 癈in acetic anhydride giving
1-[2-(1,3-dioxolan-2-yl)ethyl]-5-(4-fluorophenyl)-2-isopropyl-N,4 -diphenylpyrrole-3-carboxamide (X). The hydrolysis of the dioxolane
group of (X) with HCl yields the corresponding aldehyde (XI), which is condensed with methyl acetoacetate (XII) by means of NaH in THF affording 7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-(N-phenylcarbamoyl)pyrrol -1-yl]-5-hydroxy-3-oxoheptanoic acid methyl ester (XIII). The reduction of the carbonyl group of (XIII) with tributylborane and NaBH4 in THF gives the (3R*,5R*)-dihydroxy ester (XIV), which is saponified with NaOH in water yielding the corresponding free acid (XV). The lactonization of (XV) by heating in refluxing toluene affords the (R*,R*)-lactone (XVI) (1, 2), which is submitted to optical resolution by reaction with (R)-1-phenylethylamine (XVII) followed by fractional crystallization thus obtaining the amide (XVII) as the pure (R,R,R)-enantiomer. The hydrolysis of the amide (XVIII) with NaOH, followed by heating in refluxing toluene gives the (R,R)-lactone (XIX) (2, 3), which is finally treated first with NaOH in
methanol/water, and then with CaCl2 or calcium acetate (3, 4). 2) The condensation of the already described aldehyde (XI) with
(S)-(+)-2-acetoxy-1,1,2-triphenylethanol (XX) by means of lithium diisopropylamide (LDA) in THF gives
5-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-(N-phenylcarbamoyl)pyrrol -1-yl]-3(R)-hydroxypentanoic acid
2-hydroxy-1(S),2,2-triphenylethyl ester (XXI), which is trans-esterified with sodium methoxide in methanol/THF yielding the expected methyl ester (XXII). The condensation of (XXII) with tert-butyl acetate (XXIII) by means of LDA in THF affords
(R)-7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-(N-phenylcarbamoyl) pyrrol-1-yl]-5-hydroxy-3-oxoheptanoic acid tert-butyl ester (XXIV), which is reduced with triethylborane and NaBH4 in THF, hydrolyzed with NaOH, lactonized by heating in refluxing toluene and finally submitted to fractional crystallization in order to separate the two diastereomers of the obtained lactone, (R,R) and (R,S) (2, 3). The
(R,R)-diastereomer (XIX), already obtained, is finally treated with NaOH and then with CaCl2 (2-4). 3) The condensation of
4-cyano-3(R)-hydroxybutyric acid ethyl ester (XXV) with N,N-diphenylacetamide (R1 = R2 = Ph in XXVI) by means of LDA in THF gives 6-cyano-5(R)-hydroxy-3-oxo-N,N-diphenylhexanamide (XXVII), which is reduced with diethylmethoxyborane and NaBH4 in THF yielding 6-cyano-3(R),5(R)-dihydroxy-N,N-diphenylhexanamide (XXVIII). The protection of the two OH groups of (XXVIII) with acetone dimethylketal (XXIX) and methanesulfonic acid affords the 1,3-dioxane (XXX), which by reduction of its CN group by hydrogenation with H2 over RaNi in methanol/liquid ammonia gives (4R,6R)-2-[6-(2-aminoethyl)-2,2-dimethyl-1,3-dioxan-4-yl]-N,N -diphenylacetamide (XXXI). The cyclization of (XXXI) with 4-(4-fluorophenyl)-2-isobutyryl-4-oxo-N-phenylbutyramide (XXXII) (its synthesis is in section 6, Scheme 4) in refluxing toluene yields the protected dihydroxyheptanamide (XXXIII), which is deprotected with HCl in methanol to afford
(3R,5R)-7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-(N -phenylcarbamoyl)pyrrol-1-yl]-3,5-dihydroxy-N,N-diphenylheptanamide (XXXIV). Finally, this compound is hydrolyzed with NaOH and treated with calcium acetate in water (5). Scheme 18007203a. 4) The preceding reaction pathway can be repeated using other substituents for R1 and R2 in acetamide (XXVI) such as R1 = R2 = CH2Ph; R1 = R2 = Et; R1 = Bu, R2 = Me; R1 = t-Bu, R2 = CH2Ph; R1,R2 = -(CH2)5- (5). 5) The hydrolysis of methyl (Et or Bu)
3(R)-(tert-butyldimethylsilyloxy)-4-cyanobutyrate (XXV) with NaOH gives the corresponding free acid (XXXVI), which is condensed with malonic acid mono-tert-butyl ester magnesium salt (XXXVII) by means of carbonyldiimidazole (CDI) yielding tert-butyl
5(R)-(tert-butyldimethylsilyloxy)-6-cyano-3-oxohexanoate (XXXVIII). The desilylation of (XXXVIII) with tetrabutylammonium fluoride in acetic acid affords the expected hydroxylated ketoester (XXXIX), which is reduced with diethylmethoxyborane and NaBH4 in methanol giving tert-butyl 6-cyano-3(R),5(R)-dihydroxyhexanoate (XL). The protection of the two OH groups of (XL) with acetone dimethylketal (XXIX) and methanesulfonic acid affords the 1,3-dioxane (XLI) (6), which by reduction of its CN group by hydrogenation with H2 over
Pd/C gives intermediate (4R,6R)-2-[6-(2-aminoethyl)-2,2-dimethyl-1,3-dioxan-4-yl]acetic acid tert-butyl ester (XLII). The cyclization of (XLII) with 4-(4-fluorophenyl-2-isobutyryl-4-oxo-N-phenylbutyramide (XXXII) in refluxing toluene yields the protected dihydroxyheptanoate (XLIII), which is deprotected with HCl in methanol and finally hydrolyzed with NaOH and treated with calcium acetate in water (7). 8) The synthesis of the 4-(4-fluorophenyl)-2-isobutyryl-4-oxo-N-phenylbutyramide (XXXII) is carried out as follows: The condensation of 4-methyl-3-oxo-N-phenylpentanamide (XLIV) with benzaldehyde (XLV) gives
2-benzylidene-4-methyl-3-oxo-N-phenylpentanamide (XLVI), which is then condensed with 4-fluorobenzaldehyde (XLVII) by means of triethylamine in hot ethanol (7). 6) The (4R,6R)-2-[6-(cyanomethyl)-2,2-dimethyl-1,3-dioxan-4-yl]acetic acid tert-butyl ester (XLI) can also be obtained by reaction of (4R,6R)-2-[6-(2-hydroxyethyl)-2,2-dimethyl-1,3-dioxan-4-yl]acetic acid tert-butyl ester (XLVIII) with tosyl chloride to give the corresponding tosylate (XVIX), which is then treated with NaCN (6). 7) The tert-butyl
6-cyano-5(R)-hydroxy-3-oxohexanoate (XXXIX) can also be obtained by condensation of methyl 4-cyano-3(R)-hydroxybutyrate (L) with tert-butyl acetate (XXIII) by means of LDA in THF (6). 8) The synthesis of the 4-(4-fluorophenyl)-2-isobutyryl-4-oxo-N-phenylbutyramide (XXXII) is carried out as follows: The condensation of 4-methyl-3-oxo-N-phenylpentanamide (XLIV) with benzaldehyde (XLV) gives
2-benzylidene-4-methyl-3-oxo-N-phenylpentanamide (XLVI), which is then condensed with 4-fluorobenzaldehyde (XLVII) by means of
triethylamine in hot ethanol (7). 9) The cyclization of (XXXII) with intermediate (XLII) (preceding synthesis) in refluxing toluene yields the protected dehydroxyheptanoate (XLIII), which is deprotected with HCl in methanol and finally hydrolyzed with NaOH and treated with calcium acetate in water. References 1. Roth, B.D. (Warner-Lambert Co.). Trans-6-[2-(3- or 4-carboxamido-substd.
pyrrol-1-yl)alkyl]-4-hydroxypyran-2-one inhibitors of cholesterol synthesis. EP 247633, US 4681893. 2. Roth, B.D., Blankley, C.J., Chucholowski, A.W., Ferguson, E., Hoefle, M.L., Ortwine, D.F., Newton, R.S., Sekerke, C.S., Sliskovic, D.R., Stratton, C.D., Wilson, M.W. Inhibitors of cholesterol biosynthesis. 3. Tetrahydro-4-hydroxy-6-[2-(1H-pyrrol-1-yl)ethyl]-2H-pyran-2-one inhibitors of HMG-CoA reductase. 2. Effects of introducing substituents at positions three and four of the pyrrole nucleus. J Med Chem 1991, 34: 357-66. 3. Roth, B.D. (Warner-Lambert Co.). (R-(R*R*)-2-(4-Fluorophenyl)-beta,delta-dihydroxy-5-(1-methylethyl-3
-phenyl-4-[(phenylamino)-carbonyl]-1H-pyrrole-1-heptanoic acid, its lactone form and salts thereof. EP 409281, JP 91058967, US 5273995.
4. Milb, N., Muhammad, N.A., Weiss, J., Nesbitt, R.U. (Warner-Lambert Co.). Stable oral CI-981 formulation and process for preparing same. EP 680320, JP 96505640, WO 9416693.
5. Butler, D.E., Le, T.V., Nanninga, T.N. (Warner-Lambert Co.). Process for
trans-6-[2-(substd.-pyrrol-1-yl)alkyl]pyran-2-one inhibitors of cholesterol synthesis. US 5298627. 6. Brower, P.L., Butler, D.E., Deering, C.F., Le, T.V., Millar, A., Nanninga, T.N., Roth, B.D. The synthesis of (4R-cis)-1,1-dimethylethyl
6-cyanomethyl-2,2-dimethyl-1,3-dioxane-4-acetate, a key intermediate for the preparation of CI-981, a highly potent, tissue selective inhibitor of HMG-CoA reductase. Tetrahedron Lett 1992, 33: 2279-82. 7. Baumann, K.L., Butler, D.E., Deering, C.F., Mennen, K.E., Millar, A., Nanninga, T.N., Palmer, C.W., Roth, B.D. The convergent synthesis of CI-981, an optically active, highly potent, tissue selective inhibitor of HMG-CoA reductase. Tetrahedron Lett 1992, 33: 2283-4. 8. McKenzie, A.T. (Warner-Lambert Co.). Form III crystalline
(R-(R*,R*))-2-(4-fluorophenyl)-beta,delta-dihydroxy-5-(1-methyl-ethyl) -3-phenyl-4-((phenylamino)carbonyl)-1H-pyrrole-1-heptanoic acid hemi calcium salt (atorvastatin). WO 9703958. 9. Lin, M., Schweiss, D. (Warner-Lambert Co.). Novel process for the production of amorphous [R-(R*,R*)]-2-(4-fluorophenyl)-beta,delta-dihydroxy-5-(1-methylethyl)
-3-phenyl-4-[(phenylamino)carbonyl]-1H-pyrrole-1-heptanoic acid calcium salt (2:1). WO 9703960. 10. Briggs, C.A., Jennings, R.A., Wade, R.A., Harasawa, K., Ichikawa, S., Minohara, K., Nakagawa, S. (Warner-Lambert Co.). Crystalline
[R-(R*,R*)]-2-(4-fluorophenyl)-beta,delta-dihydroxy-5-(1-methylethyl) -3-phenyl-4-[(phenylamino)carbonyl]-1H-pyrrole-1-heptanoic acid hemi calcium salt (atorvastatin). WO 9703959.
〖来源〗
J Med Chem
〖合成路线〗
〖标题〗
Inhibitors of cholesterol biosynthesis. 3. Tetrahydro-4-hydroxy-6-[2-(1H-pyrrol-1-yl)ethyl]-2H-pyran-2-one inhibitors of HMG-CoA reductase. 2. Effects of introducing substituents at positions three and four of the pyrrole nucleus
〖合成方法〗
2) The condensation of the previously described aldehyde (XI) with (S)-(+)-2-acetoxy-1,1,2-triphenylethanol (XX) by means of lithium diisopropylamide (LDA) in THF gives
5-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-(N-phenylcarbamoyl)pyrrol-1-yl]-3(R)-hydroxypentanoic acid
2-hydroxy-1(S),2,2-triphenylethyl ester (XXI), which is trans-esterified with sodium methoxide in methanol/THF yielding the expected methyl ester (XXII). The condensation of (XXII) with tert-butyl acetate (XXIII) by means of LDA in THF affords
(R)-7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-(N-phenylcarbamoyl) pyrrol-1-yl]-5-hydroxy-3-oxoheptanoic acid tert-butyl ester (XXIV), which is reduced with triethylborane and NaBH4 in THF, hydrolyzed with NaOH, lactonized by heating in refluxing toluene and finally submitted to fractional crystallization in order to separate the two diastereomers of the obtained lactone, (R,R) and (R,S). The
(R,R)-diastereomer (XIX), already obtained, is finally treated with NaOH and then with CaCl2.
〖作者〗
Roth, B.D.; Blankley, C.J.; Chucholowski, A.W.; Ferguson, E.; Hoefle, M.L.; Ortwine, D.F.; Newton, R.S.; Sekerke, C.S.; Sliskovic, D.R.; Stratton, C.D.; Wilson, M.W.
〖参考〗
Roth, B.D.; Blankley, C.J.; Chucholowski, A.W.; Ferguson, E.; Hoefle, M.L.; Ortwine, D.F.; Newton, R.S.; Sekerke, C.S.; Sliskovic, D.R.; Stratton, C.D.; Wilson, M.W.; Inhibitors of cholesterol biosynthesis. 3. Tetrahydro-4-hydroxy-6-[2-(1H-pyrrol-1-yl)eth IĶ 셈睋서睋쓰睎쓜睎 Ʈ 0 ๙ιᇐ ꀀÑ밸-00AA004CLSID\{0E59F1D5-1FBE-11D0-8FF2-00A0D10038BC}e Ǔ ℐ ul> li>a href=
〖出处〗。